Piperacillin-tazobactam is a widely used antibiotic that can cause rare but clinically significant thrombocytopenia. The article describes the case of a 57-year-old woman with severe trauma and pulmonary infection who developed sudden severe thrombocytopenia after initiation of piperacillin-tazobactam therapy. After discontinuation of the drug, platelet counts recovered rapidly, coagulation parameters did not exclude DIC, and HIT was unlikely (4Ts score ≤3). A Naranjo score of 5 indicated a probable adverse drug reaction, flow cytometry testing for antiplatelet antibodies was negative. A review of the literature identified 23 cases where thrombocytopenia was thought to be immune-mediated, including those with negative antibody tests. Thus, negative antiplatelet antibody testing does not exclude the diagnosis of drug-induced immune thrombocytopenia (DIIT) associated with this antibiotic. A structured diagnostic approach and close platelet monitoring are required when DIIT is suspected in critically ill patients, with clinical assessment and temporal association being key.